Multiple sclerosis is an inflammatory demyelinating disease of the central nervous system that exhibits characteristics of both autoimmune and demyelinating diseases. Although mechanisms of myelin repair are engaged, remyelination often fails, especially in the chronic or progressive stages of disease. It has been hypothesized that this is due to a differentiation block to oligodendrocyte precursor cells (OPC), perhaps secondary to lack of axonal signals or to inflammatory mediators. Recent evidence implicates the canonical Wnt/-catenin signaling pathway in the block to OPC differentiation. Dr. Mike Kahn, Co-Investigator, has developed small molecule inhibitors of Wnt/-catenin signaling that have led to the discovery of a co-activator switching mechanism in the Wnt/-catenin pathway that regulates stem cell decisions to proliferation or differentiate. Preliminary data indicate tha one of these inhibitors, ICG-001, is capable of promoting OPC differentiation in vitro and, upon in vivo administration, ameliorates clinical and histopathological experimental autoimmune encephalomyelitis (EAE). In this application, experiments are proposed to investigate the full potential for ICG-001 to modify demyelinating disease, repeating and expanding the preliminary findings to additional, well-established models that replicate key features of MS pathogenesis. The primary hypothesis to be tested is that ICG-001 promotes OPC differentiation, remyelination and clinical recovery from demyelinating disease, accompanied by evidence of reduced inflammation and demyelination. In addition, we wish to establish if ICG-001 is a suitable candidate for testing as a treatment in MS patients, and thus, a future IND application for a phase I clinical trial. The research strategy is composed of three specific aims: 1) to test the hypothesis that ICG-001 promotes differentiation of primary oligodendrocyte precursor cells in vitro, 2) to test the hypothesis that ICG-001 promotes oligodendrocyte differentiation following lysolecithin-induced focal demyelination, and 3) to identify the potential for ICG-001 to promote oligodendrocyte differentiation and remyelination and alter inflammatory characteristics in classical autoimmune models of MS, experimental autoimmune encephalomyelitis (EAE). PUBLIC HEALTH RELEVANCE: In this application, we plan to test the potential of a unique new treatment, known as a Wnt inhibitor, for repair of the damage that occurs in the central nervous system in multiple sclerosis (MS), a demyelinating disease diagnosed in approximately 400,000 individuals in the United States, and 2.4 million worldwide. Since a compound similar to this Wnt inhibitor, known as ICG-001, is currently being tested in a phase I clinical trial for cancer in humans, it is possible that the insights gained can be rapidly applied to testing in patients with MS.